Xanthine is a dioxypurine that is structurally related to uric acid. Xanthine can be represented by the following structure: ##STR2##
Caffeine, theophylline and theobromine are methylated xanthines. Methylated xanthines such as caffeine and theophylline are typically used for their bronchodilating action in the management of obstructive airways diseases such as asthma. The bronchodilator effects of methylxanthines are thought to be mediated by relaxation of airway smooth muscle. Generally, methylxanthines function by inhibiting cyclic nucleotide phosphodiesterases and antagonizing receptor-mediated actions of adenosine.
Theophylline can be represented by the following structure: ##STR3##
However, when administered intravenously or orally, theophylline has numerous undesired or adverse effects that are generally systemic in nature. It has a number of adverse side effects, particularly gastrointestinal disturbances and CNS stimulation. Nausea and vomiting are the most common symptoms of theophylline toxicity. Moderate toxicity is due to relative epinephrine excess, and includes tachycardia, arrhythmias, tremors, and agitation. Severe toxicity results in hallucinations, seizures, dysrythmias and hypotension. The spectrum of theophylline toxicity can also include death.
Furthermore, theophylline has a narrow therapeutic range of serum concentrations above which serious side effects can occur. The pharmacokinetic profile of theophylline is dependent on liver metabolism, which can be affected by various factors including smoking, age, disease, diet, and drug interactions.
Generally, the solubility of methylxanthines is low and is enhanced by the formation of complexes, such as that between theophylline and ethylenediamine (to form aminophylline). The formation of complex double salts (such as caffeine and sodium benzoate) or true salts (such as choline theophyllinate) also enhances aqueous solubility. These salts or complexes dissociate to yield the parent methylxanthine when dissolved in aqueous solution. Although salts such as aminophylline have improved solubility over theophylline, they dissociate in solution to form theophylline and hence have similar toxicities. However, aminophylline has been reported to be effective in reducing the incidence of contrast nephropathy.
Dyphylline is a covalently modified derivative of xanthine (1,3,-dimethyl-7-(2,3-dihydroxypropl)xanthine. Because it is covalently modified, dyphylline is not converted to free theophylline in vivo. Instead, it is absorbed rapidly in therapeutically active form. Dyphylline has a lower toxicity than theophylline. Dyphylline can be represented by the following structure: ##STR4##
Dyphylline is an effective bronchodilator that is available in oral and intramuscular preparations. Generally, dyphylline possesses less toxic side effects than theophylline.
U.S. Pat. No. 4,031,218 (El-Antably) discloses the use of 7-(2,3-dihydroxypropyl)-1,3-di-n-propylxanthine, a derivative of theophylline, as a bronchodilator. U.S. Pat. No. 4,341,781 (Scheindlin) discloses the use of dyphylline in the treatment of psoriasis and other diseases of the skin by topical administration of dyphylline. U.S. Pat. No. 4,581,359 (Ayres) discloses methods for the management of bronchopulmonary insufficiency by administering an N-7-substituted derivative of theophylline, including dyphylline, etophylline, and proxyphylline.
A kidney stone (also called a bladder stone or cystic calculi) is an abnormal accumulation of mineral salts or crystals that separate from urine and build up on the inner surfaces of the kidney. The medical terminology for kidney stones is nephrolithiasis or renal calculi. A kidney stone can be as small as a grain of sand or as large as a golf ball. Nephrolithiasis has prevalence in the American population of about 5 cases per 1000 persons. Calcium oxalate calculi (73%) are the most common, followed by calcium phosphate and magnesium ammonium phosphate (16%), uric acid (7%) and cystine (1%) calculi. The most common sites of kidney stone impaction are a renal calyx, the ureteropelvic junction, the pelvic brim, and the ureterovesical junction.
Kidney stones may stay in the kidney and grow or may dislodge and try to pass down the narrow ureter into the bladder. About 90% of stones will pass spontaneously within three to six weeks. Most small stones pass within hours or a few days. Other stones must be removed medically. Generally, small stones can pass through the urinary system without causing problems. However, larger stones can block the flow of urine or irritate the lining of the urinary tract. If left untreated, this shut down can lead to permanent loss of finction in that kidney. Even worse, the kidney stone can even rupture the collection system of the kidney and even result in death.
Renal colic (strong kidney pain) results when the stone enters the ureters. These sharp pains may last hours or days. Symptoms include increased urination with pus and blood, pallor, nausea, and vomiting. Sometimes the patient experiences fever and chills.
If a stone will not pass by itself, it can be removed. Extracorporeal Shockwave Lithotripsy (ESWL) is a method of stone treatment where shock waves (non-electrical shocks) are passed through the patient's body. The stone is fragmented and the (smaller) fragments are passed. Ureteroscopy is a technique that involves placing a scope into the urethra, the bladder and then fmally up into the narrow ureters. This scope engages the stone and either fragments it or extracts it. The percutaneous method (PNL) involves placing a scope directly through the skin in the patient's back into the kidney. The stone may then be removed or fragmented through this scope. This technique is generally reserved for larger stones. In open surgery, a doctor actually opens up the kidney and physically takes out the stones.
Aminophylline is known to be effective in relieving biliary colic. Gladstone et al., (1944), JAMA, 126:1084-1085.
Injections of radiocontrast agents are another cause of acute decreases in renal function. Contrast associated nephropathy occurs most often in patients with chronic renal insufficiency and diabetes mellitus. Contrast-associated nephropathy is characterized by a significant rise in serum creatinine 1-5 days following intervascular contrast injection. Contrast nephropathy results in significant deterioration of renal finction in many patients. Acute intrarenal vasoconstriction contributes to the acute renal failure due to radiocontrast agents (contrast nephropathy).
Kolonko et al, (1998), J. Nephrol., 11(3):151-6 report that radiocontrast agent induced impairment of renal function can be prevented by giving theophylline before administering the radiocontrast agent. Katholi et al., (1995), Radiology, 195(1):17-22 conclude that depression of creatine clearance after administration of contrast medium can be prevented by administration of theophylline.